Journal of Lipid Research (Jun 1999)
Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin
Abstract
The concept that hepatic cholesterol synthesis regulates hepatocyte assembly and secretion of apoB-containing lipoproteins remains controversial. The present study was carried out in HepG2 cells to examine the regulation of apoB secretion by the HMG-CoA reductase inhibitor atorvastatin. ApoB accumulation in the media was decreased by 24% and 36% at 10 μm (P < 0.02) and 20 μm (P < 0.01) of atorvastatin, respectively. Atorvastatin inhibited HepG2 cell cholesterol synthesis by up to 96% (P < 0.001) and cellular cholesteryl ester (CE) mass by 54% (P < 0.001). Another HMG-CoA reductase inhibitor, simvastatin, decreased cellular cholesterol synthesis and CE mass by up to 96% (P < 0.001) and 52% (P < 0.001), respectively. However, in contrast to atorvastatin, simvastatin had no effect on apoB secretion. To characterize the reduction in apoB secretion by atorvastatin (10 μm), pulse-chase experiments were performed and the kinetic data were analyzed by multicompartmental modeling using SAAM II. Atorvastatin had no affect on the synthesis of apoB, however, apoB secretion into the media was decreased by 44% (P = 0.048). Intracellular apoB degradation increased proportionately (P = 0.048). Simvastatin (10 μm) treatment did not significantly alter either the secretion or intracellular degradation of apoB, relative to control. The kinetics of apoB degradation were best described by a rapidly and a slowly turning over degradation compartment. The effect of atorvastatin on apoB degradation was largely confined to the rapid compartment. Neither inhibitor affected apoB mRNA concentrations, however, both significantly increased LDL receptor and HMG-CoA reductase mRNA levels. Atorvastatin treatment also decreased the mRNA for the microsomal triglyceride transfer protein (MTP) by 22% (P < 0.02). These results show that atorvastatin decreases apoB secretion, by a mechanism that results in an enhanced intracellular degradation of apoB.—Wilcox, L. J., P. H. R. Barrett, and M. W. Huff. Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin. J. Lipid Res. 1999. 40: 1078–1089.
